tbuckley/cabot-search huggingface dataset:
Association Between Autism Spectrum Disorders and Cardiometabolic Diseases
Authors: Chathurika S. Dhanasekara, Dominic Ancona, Leticia Cortes, Amy Hu, Afrina H. Rimu, Christina Robohm-Leavitt, Drew Payne, Sarah M. Wakefield, Ann M. Mastergeorge, Chanaka N. Kahathuduwa
Journal: JAMA Pediatrics (2023)

Although the increased risk of obesity among individuals with autism has been well established, evidence on the association between autism, cardiometabolic disorders, and obesity remains inconclusive.
Antineutrophil cytoplasmic antibody–associated vasculitis and <scp>VEXAS</scp> syndrome: comment on the article by Muratore et al
Authors: Matthew J. Koster, Umar Ghaffar, Tanaz A. Kermani, Mrinal M. Patnaik, Ronald S. Go, Abhishek A. Mangaonkar, Kaaren K. Reichard, Horatiu Olteanu, Kenneth J. Warrington
Journal: Arthritis & Rheumatology (2023)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency
Authors: Patrick Forny, Ximena Bonilla, David Lamparter, Wenguang Shao, Tanja Plessl, Caroline Frei, Anna Bingisser, Sandra Goetze, Audrey van Drogen, Keith Harshman, Patrick G. A. Pedrioli, Cedric Howald, Martin Poms, Florian Traversi, Céline Bürer, Sarah Cherkaoui, Raphael J. Morscher, Luke Simmons, Merima Forny, Ioannis Xenarios, Ruedi Aebersold, Nicola Zamboni, Gunnar Rätsch, Emmanouil T. Dermitzakis, Bernd Wollscheid, Matthias R. Baumgartner, D. Sean Froese
Journal: Nature Metabolism (2023)

Abstract Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase ( MMUT ). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT and glutamine anaplerotic enzymes. Using stable-isotope tracing, we find that treatment with dimethyl-oxoglutarate restores deficient tricarboxylic acid cycling. Our work highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA.
Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness
Authors: Hongcheng Cheng, Yajing Qiu, Yue Xu, Li Chen, Kaili Ma, Mengyuan Tao, Luke Frankiw, Hongli Yin, Ermei Xie, Xiaoli Pan, Jing Du, Zhe Wang, Wenjie Zhu, Lu Chen, Lianjun Zhang, Guideng Li
Journal: Nature Metabolism (2023)

The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.
Enhancer–promoter interactions can bypass CTCF-mediated boundaries and contribute to phenotypic robustness
Authors: Shreeta Chakraborty, Nina Kopitchinski, Zhenyu Zuo, Ariel Eraso, Parirokh Awasthi, Raj Chari, Apratim Mitra, Ian C. Tobias, Sakthi D. Moorthy, Ryan K. Dale, Jennifer A. Mitchell, Timothy J. Petros, Pedro P. Rocha
Journal: Nature Genetics (2023)
Enhancer-instructed epigenetic landscape and chromatin compartmentalization dictate a primary antibody repertoire protective against specific bacterial pathogens
Authors: E. Mauricio Barajas-Mora, Lindsay Lee, Hanbin Lu, J. Andrés Valderrama, Elisabet Bjanes, Victor Nizet, Ann J. Feeney, Ming Hu, Cornelis Murre
Journal: Nature Immunology (2023)
Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro
Authors: Marzia Rossi, Andrea Vecchi, Camilla Tiezzi, Valeria Barili, Paola Fisicaro, Amalia Penna, Ilaria Montali, Stephane Daffis, Simon P Fletcher, Anuj Gaggar, Jonathan Medley, Michael Graupe, Latesh Lad, Alessandro Loglio, Roberta Soffredini, Marta Borghi, Teresa Pollicino, Cristina Musolino, Arianna Alfieri, Federica Brillo, Diletta Laccabue, Marco Massari, Chiara Boarini, Gianluca Abbati, Giuseppe Pedrazzi, Gabriele Missale, Pietro Lampertico, Carlo Ferrari, Carolina Boni
Journal: Gut (2023)

Exhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control infection and reconstitute antiviral function.HBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients.Severely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2.The possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability.
Effectiveness of a judo-specific injury prevention programme: a randomised controlled trial in recreational judo athletes
Authors: Amber L von Gerhardt, Guus Reurink, Gino M M J Kerkhoffs, Evert Verhagen, Kai Krabben, Jeroen Mooren, Jessica S I Gal, Arnold Brons, Ronald Joorse, Benny van den Broek, Ellen Kemler, Johannes L Tol
Journal: British Journal of Sports Medicine (2023)

Objectives To evaluate the effectiveness of a trainer-supervised judo-specific injury prevention warm-up programme on overall injury prevalence. Methods We conducted a two-arm, cluster randomised controlled trial; the Injury Prevention and Performance Optimization Netherlands (IPPON) study. Judo athletes aged≥12 years were randomised by judo school to IPPON intervention or control group who performed their usual warm-up. Primary outcome was overall injury prevalence (%) over the follow-up period (16–26 weeks) measured fortnightly with the Oslo Sports and Trauma Research Centre Questionnaire. A modified intention-to-treat analysis was performed due to COVID-19, with estimates for the primary outcome obtained using generalised linear mixed models. Secondary outcomes included: prevalence of severe injuries, overall incidence, time-loss injuries, exposure, adherence and experiences of trainers and athletes. Results 269 judo athletes (IPPON: 117, Control: 152) were included. Mean injury prevalence over 16–26 weeks was 23% (95% CI 20% to 26%) in the IPPON and 28% (95% CI 25% to 30%) in the control group. We observed no significant difference of all reported injuries (OR 0.72 in favour of the IPPON group; 95% CI 0.37 to 1.39). Secondary outcomes also demonstrated no significant differences between groups. Specifically, no significant difference of severe injuries was reported (OR 0.80 in favour of the IPPON group; 95% CI 0.36 to 1.78). All trainers and 70% of athletes perceived the IPPON intervention as successful. Conclusion The IPPON intervention did not significantly reduce the overall and severe injury prevalence. Despite this, we suggest the IPPON intervention be considered as an useful alternative to regular judo warm-up, given the high adherence and the positive clinical experiences of trainers and athletes. Trial registration number NTR7698.
Proton pump inhibitors and the risk of inflammatory bowel disease: population-based cohort study
Authors: Devin Abrahami, Richeek Pradhan, Hui Yin, Russell Yanofsky, Emily Gibson McDonald, Alain Bitton, Laurent Azoulay
Journal: Gut (2023)

Objective To determine whether the use of proton pump inhibitors (PPIs) compared with the use of histamine-2 receptor antagonists (H2RAs) is associated with an increased risk of inflammatory bowel disease (IBD). Design Population-based cohort study designed to address the impact of protopathic bias. Setting General practices contributing data to the UK Clinical Practice Research Datalink GOLD. Participants 1 498 416 initiators of PPIs and 322 474 initiators of H2RAs from 1 January 1990 to 31 December 2018, with follow-up until 31 December 2019. Patients were analysed according to the timing of the IBD diagnosis after treatment initiation (early vs late). Main outcome measures Standardised morbidity ratio weighted Cox proportional hazards models were used to estimate marginal HRs and 95% CIs. In the early-event analysis, IBD diagnoses were assessed within the first 2 years of treatment initiation, an analysis subject to potential protopathic bias. In the late-event analysis, all exposures were lagged by 2 years to account for latency and minimise protopathic bias. Results In the early-event analysis, the use of PPIs was associated with an increased risk of IBD within the first 2 years of treatment initiation, compared with H2RAs (HR 1.39, 95% CI 1.14 to 1.69). In contrast, the use of PPIs was not associated with an increased risk of IBD in the late-event analysis (HR 1.05, 95% CI 0.90 to 1.22). The results remained consistent in several sensitivity analyses. Conclusions Compared with H2RAs, PPIs were not associated with an increased risk of IBD, after accounting for protopathic bias.
Diagnostic approach to lower airway dysfunction in athletes: a systematic review and meta-analysis by a subgroup of the IOC consensus on ‘acute respiratory illness in the athlete’
Authors: Tonje Reier-Nilsen, Nicola Sewry, Bruno Chenuel, Vibeke Backer, Kjell Larsson, Oliver J Price, Lars Pedersen, Valerie Bougault, Martin Schwellnus, James H Hull
Journal: British Journal of Sports Medicine (2023)

Objectives To compare the performance of various diagnostic bronchoprovocation tests (BPT) in the assessment of lower airway dysfunction (LAD) in athletes and inform best clinical practice. Design Systematic review with sensitivity and specificity meta-analyses. Data sources PubMed, EBSCOhost and Web of Science (1 January 1990–31 December 2021). Eligibility criteria Original full-text studies, including athletes/physically active individuals (15–65 years) who underwent assessment for LAD by symptom-based questionnaires/history and/or direct and/or indirect BPTs. Results In 26 studies containing data for quantitative meta-analyses on BPT diagnostic performance (n=2624 participants; 33% female); 22% had physician diagnosed asthma and 51% reported LAD symptoms. In athletes with symptoms of LAD, eucapnic voluntary hyperpnoea (EVH) and exercise challenge tests (ECTs) confirmed the diagnosis with a 46% sensitivity and 74% specificity, and 51% sensitivity and 84% specificity, respectively, while methacholine BPTs were 55% sensitive and 56% specific. If EVH was the reference standard, the presence of LAD symptoms was 78% sensitive and 45% specific for a positive EVH, while ECTs were 42% sensitive and 82% specific. If ECTs were the reference standard, the presence of LAD symptoms was 80% sensitive and 56% specific for a positive ECT, while EVH demonstrated 65% sensitivity and 65% specificity for a positive ECT. Conclusion In the assessment of LAD in athletes, EVH and field-based ECTs offer similar and moderate diagnostic test performance. In contrast, methacholine BPTs have lower overall test performance. PROSPERO registration number CRD42020170915.
Association of clinically significant obstructive sleep apnoea with risks of contracting COVID-19 and serious COVID-19 complications: a retrospective population-based study of health administrative data
Authors: Tetyana Kendzerska, Marcus Povitz, Andrea S Gershon, Clodagh M Ryan, Robert Talarico, Dennys Andrea Franco Avecilla, Rebecca Robillard, Najib T Ayas, Sachin R Pendharkar
Journal: Thorax (2023)

Rationale/objectives Despite plausible pathophysiological mechanisms, more research is needed to confirm the relationship between obstructive sleep apnoea (OSA) and the risk of COVID-19 infection or COVID-19-related serious complications. Methods We conducted a retrospective population-based cohort study using provincial health administrative data (Ontario, Canada). Adults with physician-diagnosed OSA who received positive airway pressure therapy in the 5 years prepandemic ( OSA group ) were propensity score matched by baseline characteristics to individuals in the general population at low risk of OSA ( non-OSA group ) using inverse probability of treatment weighting. Weighted HRs of (1) a positive COVID-19 test and (2) COVID-19-related emergency department (ED) visits, hospitalisations, intensive care unit (ICU) admissions and mortality, within 12 months of pandemic onset, were compared between groups. We also evaluated the impact of comorbid cardiometabolic or chronic airways disease. Results We identified and matched 324 029 individuals in the OSA group to 4 588 200 individuals in the non-OSA group. Compared with the non-OSA group, those in the OSA group were at a greater hazard of testing positive for COVID-19 (HR=1.17, 95% CI 1.13 to 1.21), having a COVID-19-related ED visit (HR=1.62, 95% CI 1.51 to 1.73), hospitalisation (HR=1.50, 95% CI 1.37 to 1.65) or ICU admission (HR=1.53, 95% CI 1.27 to 1.84). COVID-19-related 30-day mortality was not different (HR=0.98, 95% CI 0.82 to 1.16). We found that for the OSA group, comorbid airways disease but not cardiometabolic conditions increased the hazards of COVID-19-related outcomes, including mortality. Conclusion In this large population-based study, we demonstrated that a recent diagnosis of OSA requiring treatment was associated with an increased hazard of testing positive for COVID-19 and serious COVID-19-related complications, particularly in those with co-existing chronic airways disease.
Targeting m<sup>6</sup>A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer
Authors: Yi Bao, Jianning Zhai, Huarong Chen, Chi Chun Wong, Cong Liang, Yanqiang Ding, Dan Huang, Hongyan Gou, Danyu Chen, Yasi Pan, Wei Kang, Ka Fai To, Jun Yu
Journal: Gut (2023)

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Review of the British Thoracic Society Winter Meeting 23 November 2022 23–25 November 2022
Authors: Tom Ward, Akhilesh Jha, Enya Daynes, Jodie Ackland, James D Chalmers
Journal: Thorax (2023)

The British Thoracic Society Winter Meeting at the QEII Centre in London provided the first opportunity for the respiratory community to meet and disseminate research findings face to face since the start of the COVID-19 pandemic. World-leading researchers from the UK and abroad presented their latest findings across a range of respiratory diseases. This article aims to represent the range of the conference and as such is written from the perspective of a basic scientist, a physiotherapist and two doctors. The authors reviewed showcase sessions plus a selection of symposia based on their personal highlights. Content ranged from exciting new developments in basic science to new and unpublished results from clinical trials, delivered by leading scientists from their fields including former deputy chief medical officer Professor Sir Jonathan Van-Tam and former WHO chief scientist Dr Soumya Swaminathan.
The epidemiology, healthcare and societal burden of basal cell carcinoma in Wales 2000–2018: a retrospective nationwide analysis
Authors: Nader Ibrahim, Matthew Jovic, Stephen Ali, Namor Williams, John A G Gibson, Rowena Griffiths, Thomas D Dobbs, Ashley Akbari, Ronan A Lyons, Hayley A Hutchings, Iain S Whitaker
Journal: British Journal of Dermatology (2022)

Basal cell carcinoma (BCC) represents the most commonly occurring cancer worldwide within the white population. Reports predict 298 308 cases of BCC in the UK by 2025, at a cost of £265-366 million to the National Health Service (NHS). Despite the morbidity, societal and healthcare pressures brought about by BCC, routinely collected healthcare data and global registration remain limited.To calculate the incidence of BCC in Wales between 2000 and 2018 and to establish the related healthcare utilization and estimated cost of care.The Secure Anonymised Information Linkage (SAIL) databank is one of the largest and most robust health and social care data repositories in the UK. Cancer registry data were linked to routinely collected healthcare databases between 2000 and 2018. Pathological data from Swansea Bay University Health Board (SBUHB) were used for internal validation.A total of 61 404 histologically proven BCCs were identified within the SAIL Databank during the study period. The European age-standardized incidence for BCC in 2018 was 224.6 per 100 000 person-years. Based on validated regional data, a 45% greater incidence was noted within SBUHB pathology vs. matched regions within SAIL between 2016 and 2018. A negative association between deprivation and incidence was noted with a higher incidence in the least socially deprived and rural dwellers. Approximately 2% travelled 25-50 miles for dermatological services compared with 37% for plastic surgery. Estimated NHS costs of surgically managed lesions for 2002-2019 equated to £119.2-164.4 million.Robust epidemiological data that are internationally comparable and representative are scarce for nonmelanoma skin cancer. The rising global incidence coupled with struggling healthcare systems in the post-COVID-19 recovery period serve to intensify the societal and healthcare impact. This study is the first to demonstrate the incidence of BCC in Wales and is one of a small number in the UK using internally validated large cohort datasets. Furthermore, our findings demonstrate one of the highest published incidences within the UK and Europe.
Tumor Microenvironment Responsive Hollow Nanoplatform for Triple Amplification of Oxidative Stress to Enhance Cuproptosis‐Based Synergistic Cancer Therapy
Authors: Weijun Xu, Yaping Wang, Guanghui Hou, Jinlei Wang, Taibing Wang, Junmin Qian, Aili Suo
Journal: Advanced Healthcare Materials (2023)

Cuproptosis is a recently discovered form of programmed cell death and shows great potential in cancer treatment. Herein, a copper-dithiocarbamate chelate-doped and artemisinin-loaded hollow nanoplatform (HNP) is developed via a chelation competition-induced hollowing strategy for cuproptosis-based combination therapy. The HNP exhibits tumor microenvironment-triggered catalytic activity, wherein liberated Cu2+ catalyzes artemisinin and endogenous H2 O2 to produce C-centered radicals and hydroxyl radicals, respectively. Meanwhile, the disulfide bonds-rich HNP can deplete intracellular glutathione, thus triply amplifying tumor oxidative stress. The augmented oxidative stress sensitizes cancer cells to the cuproptosis, causing prominent dihydrolipoamide S-acetyltransferase oligomerization and mitochondrial dysfunction. Moreover, the HNP can activate ferroptosis via inhibiting GPX4 activity and trigger apoptosis via dithiocarbamate-copper chelate-mediated ubiquitinated proteins accumulation, resulting in potent antitumor efficacy. Such a cuproptosis/ferroptosis/apoptosis synergetic strategy opens a new avenue for cancer therapy.
Heart–gut microbiota communication determines the severity of cardiac injury after myocardial ischaemia/reperfusion
Authors: Jinxuan Zhao, Qi Zhang, Wei Cheng, Qing Dai, Zhonghai Wei, Meng Guo, Fu Chen, Shuaihua Qiao, Jiaxin Hu, Junzhuo Wang, Haiting Chen, Xue Bao, Dan Mu, Xuan Sun, Biao Xu, Jun Xie
Journal: Cardiovascular Research (2023)

Recent studies have suggested a key role of intestinal microbiota in pathological progress of multiple organs via immune modulation. However, the interactions between heart and gut microbiota remain to be fully elucidated. The aim of the study is to investigate the role of gut microbiota in the post-ischaemia/reperfusion (I/R) inflammatory microenvironment.Here, we conducted a case-control study to explore the association of gut bacteria translocation products with inflammation biomarkers and I/R injury severity in ST-elevation myocardial infarction patients. Then, we used a mouse model to determine the effects of myocardial I/R injury on gut microbiota dysbiosis and translocation. Blooming of Proteobacteria was identified as a hallmark of post-I/R dysbiosis, which was associated with gut bacteria translocation. Abrogation of gut bacteria translocation by antibiotic cocktail alleviated myocardial I/R injury via mitigating excessive inflammation and attenuating myeloid cells mobilization, indicating the bidirectional heart-gut-microbiome-immune axis in myocardial I/R injury. Glucagon-like peptide 2 (GLP-2), an endocrine peptide produced by intestinal L-cells, was used in the experimental myocardial I/R model. GLP-2 administration restored gut microbiota disorder and prevented bacteria translocation, eventually attenuated myocardial I/R injury through alleviating systemic inflammation.Our work identifies a bidirectional communication along the heart-gut-microbiome-immune axis in myocardial I/R injury and demonstrates gut bacteria translocation as a key regulator in amplifying inflammatory injury. Furthermore, our study sheds new light on the application of GLP-2 as a promising therapy targeting gut bacteria translocation in myocardial I/R injury.